Since the beginning of this project we have screened over 2200 subjects for this study. We have enrolled approximately 135 youth with bipolar disorder (BD), 130 subjects at risk for BD because they have a parent or sibling with the illness, and 120 adults with BD. This year, approximately 20 new subjects were enrolled. This year we continued our work designed to identify the brain mechanisms underlying BD in children; compare brain function in youth and adults with BD in order to begin to understand how the illness develops over time; and compare brain function in youth at familial risk for BD to those with BD and those at low risk, in order to facilitate the eventual development of preventive interventions. In terms of our work on the brain mechanisms mediating BD, much of that work consists of, not only comparing youth with BD to healthy youth, but also comparing youth with BD to those with severe, chronic irritability (the so-called severe mood dysregulation, or SMD, population, see MH002786-07). It is important to compare youth with BD and those with SMD because the latter frequently receive the diagnosis of BD in the community, despite not having a history of manic episodes. Indeed, this year we published a paper demonstrating that the rate of discharges for pediatric bipolar disorder was 12.5 times higher in the US than England (compared to 3.9 times higher in the US than England for other psychiatric diagnoses). This potential misdiagnosis is important from a therapeutic and public health perspective. That is, compared to severe, chronic irritability, BD in youth is treated with more toxic medications. Therefore, it is important to identify accurately youth with BD and not extend the boundaries of the diagnosis inappropriately. In addition to comparing BD with SMD youth, consistent with the new Research Domain Criteria (RDoC) approach of the NIMH, this year we began to include additional comparison patient populations in our studies, including those with attention deficit hyperactivity disorder (ADHD) and anxiety disorders. Not only do these populations share with those with BD (and SMD) deficits in attentional and emotional control, but indeed these are the two most common comorbid illnesses in youth with BD. We are currently gathering functional neuroimaging data on these groups on several tasks that follow directly from previous work. Specifically, we are using an implicit face emotion processing (i.e., gender identification) task and a task designed to identify the mechanisms underlying increased variability in reaction time (generally thought to be an indicator of attentional lapses). We have focused on these tasks because they relate to the face emotion processing and sustained attention deficits that we and others have identified in both youth and adults with BD, and in youth at risk for the illness (the latter in a paper published this year). Whereas, in prior work, our goal was to include approximately 20 subjects per group in each study, given concerns about Type I errors in neuroimaging studies in psychiatry and the fact that we are testing hypotheses across multiple groups, in our current studies we aim to recruit at least 40 subjects in each group. Recruitment for these two studies is approximately 40% complete. One notable feature of our work is our recruitment, not only of children with BD, but also adults with the illness and unaffected youth at risk for the illness (as well as appropriate healthy comparison groups). This strategy allows us to identify possible pathophysiological mechanisms present before the onset of illness as well as across the developmental spectrum in affected individuals. Hence, we published two papers this year that complemented our previous work showing that youth with BD fail to modulate amygdala activity appropriately when viewing angry faces. Specifically, we found that this deficit is also present in adults with BD and unaffected youth at risk for the illness. Developmental differences were found, however, in subgenual cingulate modulation in response to angry faces. In addition, we found that both youth with BD and those at risk for the illness had decreased modulation of the inferior frontal gyrus (as well as the amygdala) in response to angry faces. Another, related psychological process where we were able to show continuity in deficits across the developmental and pathological spectrum in BD concerns encoding of emotional faces. In prior work, we have demonstrated a neural and behavioral deficit in emotional face encoding, and this year we published two papers demonstrating similar behavioral deficits in both adults with BD and in those at risk for the illness. Neurally, both adults and youth with BD showed occipital dysfunction during emotional face encoding, whereas youth with or at risk for the illness also showed dysfunction in the parahippocampal gyrsu. We have also continued to establish the relationships that would allow us to assess Amish children at risk for BD, and that work is progressing.